Toxicology of Industrial Compounds

64 METABOLISM OF REACTIVE CHEMICALS
toxic to proximal renal tubules. The nephrotoxic effect of o-bromophenol
and bromo hydroquinone was found to be considerably higher, indicating
that these compounds were situated along the main bioactivation route
(Monks et al., 1985). Subsequent elegant work by Monks and Lau has
shown that in fact the nephrotoxicity is caused by the glutathione
derivatives of bromohydroquinone (Lau and Monks, 1990). Interestingly,
the relative toxicity of the quinoneglutathione conjugates increases as the
extent of glutathione addition increases, i.e. the diglutathionyl derivative is
more toxic than the monoconjugate (Monks et al., 1988b). The tissue
selectivity is a consequence of their targeting to renal proximal tubule cells
by the brushborder -glutamyl transpeptidase. AT-125, a selective inhibitor
of this enzyme in vivo, protects the kidney from the toxic effects of the
conjugates. The toxicity of these hydroquinone conjugates is apparently
not mediated by cysteine conjugate β-lyase catalyzed formation of thiols.
The inhibitor of the lyase, amino-oxyacetic acid, had only minor effects on
the extent of toxicity, and the putative product, 6-bromo-2,5dihydroxythiophenol,
needed activation by oxidation before it exerted any
biological effect (Monks et al., 1990b). Thus, the effects of these
conjugates apparently are a consequence of their oxidation to the
corresponding quinones.
Several isomers of 2-bromo-glutathionyl as well as the
bromodiglutathionyl hydroquinones were isolated and tested. Instead of a
direct correlation of toxicity with the electrochemical properties of these
compounds, it was found that the diglutathionyl derivative, which is by far
the most toxic, was the most stable to oxidation at pH 7.4 (Monks and
Lau, 1990). The paradox was clarified by Monks and Lau by determining
the oxidation potentials of the breakdown products for the mercapturic
acid pathway: hydrolysis of the glutathione moiety gives rise to the cysteine
derivative, which is more readily oxidized than the parent compound
(Monks and Lau, 1990). Apparently two detoxication pathways are
possible for these cysteine derivatives: N-acetylation results in formation of
the mercapturic acid which again is relatively resistant to oxidation, but
oxidative cyclization of cysteinylglycine and cysteine derivatives has been
found to give 1,4-benzothiazines, which do not possess any apparent toxic
properties (Monks and Lau, 1990). The action of -glutamyl
transpeptidase can thus result in both activation as found for 2bromohydroquinone
derivatives, but also in detoxication as was observed
for 2,5-dichloro-3-(glutathion-S-yl)hydroquinone and 2,5,6-trichloro-3glutathion-S-yl)hydroquinone
(Mertens et al., 1991). The ease with which
the 1,4-benzothiazines are formed is very likely the determining factor in this
case. A similar pathway has been worked out for p-aminophenol, a known
nephrotoxic metabolite of acetaminophen (Eckert et al., 1989, 1990).
Bioactivation of halogenated benzenes has long been thought to be the
result of oxidation to an epoxide. However, recent studies have shown that